Abelacimab Reduces Thrombus Propagation in a Baboon Model of Vascular Graft Thrombosis

Background: Factor XI (FXI) inhibition demonstrated strong efficacy in preventing thrombus formation in preclinical and clinical models of arterial and venous thrombosis. However, the effect of FXI inhibition in halting the progression of a formed clot remains largely unknown. Aims: This study aims to test whether abelacimab, a dual-acting FXI and activated FXI (FXIa) monoclonal antibody, is effective in halting clot formation and downstream growth when administered before or during active clot formation in an established baboon femoral arterio-venous (AV) shunt model. Methods: Three baboons had a chronic femoral AV shunt put in place; platelet and fibrin deposition inside and distal to collagen- or collagen + tissue factor (TF)-coated vascular grafts were measured at baseline (control), in a therapeutic setting, where abelacimab (1 mg/kg, intravenously) was administered 30 minutes after thrombus initiation, and in a preventative setting within the first 48 h and 1 week (144 - 216 h) post-administration. Pharmacodynamic effect was measured by activated partial thromboplastin time (aPTT). Results: Consistent with its half-life of 20 to 30 days, single iv administration of abelacimab at a dose of 1 mg/kg resulted in long-lasting (> 4-week) aPTT prolongation (> 2-fold). Administration of abelacimab 30 minutes after initiation of thrombosis using grafts coated either with collagen or with collagen + TF quickly halted downstream propagation of platelet and fibrin deposition compared to control. Further, downstream propagation of platelet and fibrin deposition was markedly reduced when clotting was induced by collagen, or collagen + tissue factor after abelacimab administration. Conclusions: These data suggest that abelacimab, a dual-acting anti-FXI/FXIa monoclonal antibody with a single long-lasting iv injection has the potential to slow down the growth and reduce the size of thrombi when admistered before or after clot induction. Data indicate a potential for therapeutic benefit of targeting FXI both in therapeutic and preventive settings. Sponsored by: Anthos Therapeutics Inc., 55 Cambridge Parkway, Suite 103, Cambridge, MA 02142 Figure 1 Figure 1. Disclosures Wallisch: Aronora Inc,: Current Employment. Khder: Anthos Therapeutics: Consultancy; Novartis: Current equity holder in publicly-traded company, Other: Retiree. Bloomfield: Anthos Therapeutics: Current Employment. Gruber: Aronora Inc.: Current Employment, Current equity holder in publicly-traded company; Oregon Health and Science University: Current Employment.

Effects of Cryofrequency at Dermal and Hypodermic Level: Case Study

Background: Cryofrequency consists of the combination of cryotherapy and radiofrequency, acting simultaneously in the treatment of flaccidity and localized adiposity. Objective: To investigate the effects of cryofrequency at the dermal and hypodermic levels. Materials and methods: This is a case study, composed of one woman of 39-year-old, with interest to perform abdominoplasty surgery, presenting adiposity and flaccidity located in infra-umbilical region. Its treatment consists of eight cryofrequence applications. Results: There was reduction of 7 cm on supra-umbilical plicometry and 6 cm on infra-umbilical; a decrease of 2.7 kg of body weight. The ultrasound data show a decrease of 0.6 mm, in the thickness of the adipose layer. In the histological analysis: thicker epidermis, with more layers and dermis with greater number of fibroblasts and inflammatory cells, greater quantity of neoformed collagen tissue. Conclusion: The application of cryofrequence promoted reduction of adipose tissue and increased production of collagen. Level of Evidence: Level III, case-control study.

Electrospun PLGA and PLGA/gelatin scaffolds for tubularized urethral replacement: Studies in vitro and in vivo

To investigate the biocompatibility of polylactic acid-glycolic acid copolymer (PLGA) and PLGA/gelatin scaffolds and their suitability for tubular urethral replacement in a canine model. PLGA and PLGA/gelatin scaffolds was constructed by electrospinning. Microstructural differences between the scaffolds was examined by Scanning electron microscopy (SEM) followed by mechanical properties testing. Biocompatibility of the material was evaluated using SEM 4, 8, 12 and 72 h after PLGA and PLGA/gelatin scaffolds co-culture with urothelial cells. And confocal analysis was also used to showed the cell adhesive and growth at 12 h. Approximately 2 cm of the anterior urethra of twelve dogs were removed and replaced with a scaffold. After the surgery for 1 month performed urethrography and for 3 month perform hematoxylin–eosin (H&E) and Masson. The results indicated that PLGA and PLGA/gelatin scaffolds had a void microfilament structure, similar to that of normal acellular matrix tissue. And the tensile strength was decreased whereas the tensile deformation and suture retention strength was increased in PLGA/gelatin scaffolds compared to that in PLGA scaffolds Urothelial cells grew well on both scaffolds. Postoperatively, animals recovered well and urinated spontaneously. However, urethrography showed varying degrees of urethral strictures in the reconstructed urethras. H&E and Masson showed that multilayer urothelial cells were formed in both the proximal and distal segments of the reconstructed urethras but without continuity. There was a small amount of smooth muscle and blood vessels under the epithelium, but regenerative urothelial cells at the midpoint of the reconstructed segment did not continue. Lots of lymphocyte infiltration was observed under the epithelium, some collagen tissue was deposited under the neo-urethral epithelium were observed. In conclusion, PLGA and PLGA/gelatin scaffolds are not suitable for tubularized urethral replacement in the canine model.

Infrequent association of two rare diseases: amniotic band syndrome and osteogenesis imperfecta

Objectives Amniotic band syndrome and osteogenesis imperfecta are two distinct diseases that develop due to structural defects of the collagen protein. In our paper, we report the concurrence of these two diseases rarely seen in the newborn period. Case presentation A female infant born at 33rd gestational week was found to have constrictive bands in her right lower extremity and flexion contractures in distal joints of lower and upper extremities due to amniotic bands in postnatal physical examination. While being treated for respiratory difficulty, she was diagnosed with osteogenesis imperfecta and treated with bisphosphonates upon being found to suffer bilateral humeral fractures on the sixth day of life. She received respiratory support with mechanical ventilation due to respiratory tract complications related to osteogenesis imperfecta and died on the 384th day of life. Conclusions One should bear in mind that other collagen tissue diseases may accompany the amniotic band syndrome; this possibility should be definitely pursued if clinical suspicion exists.

Can NLR, PLR and LMR be used as prognostic indicators in patients with pulmonary embolism? Author’s reply on commentary

We appreciate the comments made by Dr Bedel and colleagues. NLR, PLR and LMR are affected by various diseases such as oncological, collagen tissue, inflammatory, or severe renal/liver diseases [1]. Because of this, we have listed some of the above-mentioned disorders in the tables. Hematological diseases, collagen tissue disease, inflammatory diseases, congenital heart disease, or severe renal/liver disease were therefore excluded from the study. However, the presence of malignancy did not affect our results in regression analysis.Platelets swell until 120 minutes in ethylene diamine tetra acetic (EDTA) and until 60 minutes in citrate [2]. Authors suggest that optimal measuring time should not exceed 120 minutes. The blood samples of the patients were taken within 1 hour after their emergency admission. All blood samples in our study were tested within 1 hour of collection [3]. We used EDTA for whole blood anticoagulation. The mean duration of symptoms prior to admission was 5.04 ± 6.9 days. The drugs such as corticosteroids affect inflammatory parameters. Therefore, we excluded inflammatory diseases without emphasizing corticosteroids or other anti-inflammatory drugs.

Intrathrombus Fibrin Attenuates Spatial Sorting of Phosphatidylserine Exposing Platelets during Clotting Under Flow

Background As thrombosis proceeds, certain platelets in a clot expose phosphatidylserine (PS) on their outer membrane. These PS+ platelets subsequently sort to the perimeter of the mass via platelet contraction. It remains unclear how thrombin and fibrin may alter PS+ platelet sorting within a clot. Objective We investigated the role of fibrin in PS+ platelet sorting. Methods We used an 8-channel microfluidic assay of clotting over collagen (±tissue factor) at 100 s−1 initial wall shear rate. Temporal PS+ platelet sorting was measured using a Pearson's correlation coefficient between the annexin V distribution in a clot at 9 versus 15 minutes. Spatial PS+ platelet sorting was measured using an autocorrelation metric of the final annexin V distribution. Results By 6 minutes, PS+ platelets were distributed throughout the platelet deposits and became highly spatially sorted by 15 minutes when thrombin and fibrin were blocked with Phe-Pro-Arg-chloromethylketone (PPACK). Fibrin polymerization (no PPACK) attenuated temporal and spatial PS sorting and clot contraction. With Gly-Pro-Arg-Pro (GPRP) added to block fibrin polymerization, PS sorting was prominent as was clot contraction. Exogenously added tissue plasminogen activator drove fibrinolysis that in turn promoted clot contraction and PS sorting, albeit to a lesser degree than the PPACK or GPRP conditions. Clots lacking fibrin displayed 3.6 times greater contraction than clots with fibrin. Conclusion PS sorting correlated with clot contraction, as previously reported. However, fibrin inversely correlated with both percent contraction and PS sorting. Fibrin attenuated clot contraction and PS sorting relative to clots without fibrin.

Multivariate analysis reveals activation-primed fibroblast geometric states in engineered 3D tumor microenvironments

We mimic the tumor-stroma using 3D collagen tissue models of malignant breast cancer spheroids and fibroblasts to understand the factors that contribute to the selective activation of subsets of the stromal fibroblast population. Multiparametric analysis of single cells revealed that such selective activation is coupled to cell geometric states.